Derivatives of tryptamine 1
have been synthesized from substituted anilines. Some pertinent anilines are prepared from 4-nitro benzyl chloride (precursors for anti migraine pharmaceuticals such as Sumatriptan 2 see: DE 3,320,521, U.S. Pat. No. 4,816,470, Almotriptan 3 see: Res. Discl. 1998, 412, 1088, Rizatriptan 4 see: EP 0497512A2) or Zolmitriptan 5 from 4-nitro phenyl alanine see: WO 91/18897.

A variety of strategies have been disclosed for the conversion of the anilines 2, 3, 4 or 5 into the related tryptamine derivative 1. In the most common approach (scheme 2), the aniline A is converted into the corresponding phenyl hydrazine B. This is then reacted with a 4-halogeno-butyraldehyde derivative C (e.g. the dimethyl acetal (see: U.S. Pat. No. 4,816,470) or the sodium sulfite addition product (see: EP 462 837 A2 or U.S. Pat. No. 5,103,020)) or with a derivative of 4-amino butyraldehyde to give tryptamine D. Methylation of the amine of D provides the corresponding drug H. Alternatively, aniline A may be converted into indole E. A variety of pathways for the subsequent conversion of E into H is disclosed in U.S. Pat. No. 5,037,845.

One important problem regarding these approaches is the conversion of aniline A into phenyl hydrazine B. The reduction of the diazonium salt derived from A has been performed using tin(II)chloride in a three to five-fold excess. A range of environmentally more suitable reducing agents has been identified, and is claimed in patent application WO 01/34561.
For a detailed account of problems in the preparation of the phenyl hydrazine that is derived from 2 and its transformation into Sumatriptan see: Heterocycles 1998, 48, 1139. Similar problems can be expected for phenyl hydrazines that are derived from anilines 3, 4, and 5. Thus, the use of α-keto-δ-valerolactone as the carbonyl component for the Fischer-cyclisation has been suggested as an alternative, see: SK 280586B (Applicant: QUMICA SINT S A (ES); VITA INVEST, Publication date 2000-4-10).

A quite different approach to synthesize Sumatriptan also requires aniline 2, but the preparation of the phenyl hydrazine is avoided, see: Heterocycles 2000, 53, 665. Here, the diazonium salt from 2 is reacted with a β-ketocarboxylic acid ester, and the formed hydrazone is cyclised to the indole 2-carboxylic acid which is decarboxylated to a derivative of 1.

A major problem of the Fischer indolisation is that frequently only low yields of the indole are obtained due to the lack of stability of the product under the rather strongly acidic reaction conditions. Moreover, a problem of the Grandberg indolisation is that the reductive dimethylation of the primarily formed tryptamine in an alternative way is prone to low yields as side reactions such as formation of carbazoles and methylation of the indole nitrogen can take place. A solution to both of these problems is provided by using a derivative of N,N-dimethyl-4-aminobutyraldehyde in a modified Fischer indolisation protocol, see: J. Org. Chem. 1994, 59, 3738.
In all synthesis variants for derivatives of tryptamine 1 presented so far, the nature of the final product is determined early at the aniline stage. The final product is then obtained through the identical steps of hydrazine synthesis and Fischer indole cyclisation with all the described limitations. The present invention describes a route to late common intermediates for the synthesis of derivatives of tryptamine such as 1 which avoids both the synthesis of phenyl hydrazones and variations of the Fischer indolisation.
The reaction of isatin (or a derivative) with malonic acid in acetic acid, either in the presence or absence of sodium acetate, furnishes the quinolone carboxylic acid 6 instead of the expected product 7, see J. Chem. Soc. 1926, 2902 and Chem. Ber. 1914, 47, 354.

However, compounds such as 7 are known, and have been prepared for example by reacting isatin or a derivative of it with the Reformatzky reagent of a derivative of bromo acetic acid, see Chem. Ber. 1962, 95, 1138 or Tetrahedron 1967, 23, 901 or with a 15-fold excess of the lithium enolate of tert-butyl acetate, see J. Org. Chem. 1988, 53, 2844. Derivatives of 7 also have been prepared by the condensation of an isatin with methyl acetamidate and subsequent hydrolysis, see Liebigs Ann. Chem. 1967, 701, 139 or by the oxidation of the enolate of a 3-methoxycarbonylmethyl-2-oxo-2,3-dihydro-1H-indol-5-yl derivative with Davies reagent, see Heterocycles 1998, 47, 49.
Analogues of 7 have been obtained when a derivative of isatin wherein R2 is a substitutent hydrogen or ethyl was reacted with malonic acid in pyridine (see Garden et al., Tetrahedron 58, 8399-8412 (2002)). In this case the pyridinium salt 8 was obtained, from which the corresponding acid 9 was obtained simply by acidification with hydrochloric acid.
9 was then transformed into the corresponding ester in the presence of methanol and the ester then reduced with sodium borohydride to yield the corresponding tryptophyl 9a:

However, it was observed that when R2 is hydrogen (non-N-alkylated isatin) the corresponding esterification does not work. Therefore an alternative procedure employing the potassium salt of the mono-ethyl malonyl ester with 7-ethylisation in a mixture of pyridine, acetic acid and ethanol under reflux was used which gave the corresponding ester that could then be reduced.